As life expectancy increases Alzheimer's disease (AD) is becoming a major health problem in the western world. There has been intensive research aimed at identifying a reliable cure or preventive measures for the disease, so far without success.
Currently there are two mainstream therapeutic approaches to the treatment of Alzheimer's disease. The first is treatment with acetylcholine esterase inhibitors, which reduce the effects of neuron loss in the central nervous system and therefore provide some symptomatic relief for the cognitive defects. However, this approach is appropriate only in those patients in which there is substantial functional reserve left in the brain.
The second approach is to reduce the amount of or stop the deposition of beta-amyloid plaques in the brain. The main drawback of this approach is that amyloid deposition is not the cause but rather a consequence of Alzheimer's disease, and the accumulation of this protein does not have any effect on the cognitive status or functional capacity of the brain.
In recent years it is becoming more widely accepted that the pathogenic basis of Alzheimer's disease is the aberrant re-entry of different neuronal populations into the cell division cycle (Nagy Z, Esiri M M and Smith A D (1998) Neuroscience 84: 731-739). In healthy elderly individuals rapid cell cycle arrest and re-differentiation may follow this cell cycle re-entry. In contrast, in individuals with Alzheimer's disease the regulatory mechanisms appear to fail and the neurons progress into the late stages of the cell cycle leading to the accumulation of AD-related pathology and/or neuronal death (Nagy Z, Esiri M M and Smith A D (1998) Neuroscience 84: 731-739).
Studies by the present inventors and others indicate that the cell cycle regulatory failure in Alzheimer's disease occurs at the G1/S transition checkpoint (Arendt T, Rodel L, Gartner U and Holzer M (1996) Neuroreport 7: 3047-9). Previous studies on fibroblasts and lymphocytes from Alzheimer's disease patients indicate that the regulation of the cell division cycle might be disrupted in cells other than neurons in this condition (Eckert A, Hartmann H, Forstl H and Muller W E (1994) Life Sci 55: 2019-29; Fischman H K, Reisberg B, Albu P, Ferris S H and Rainer J D (1984) Biol Psychiatry 19: 319-27; Tatebayashi Y, Takeda M, Kashiwagi Y, Okochi M, Kurumadani T, Sekiyama A, Kanayama G, Hariguchi S and Nishimura T (1995) Dementia 6: 9-16). It is also known that Alzheimer's disease patients are more prone to some forms of cancer (Burke W J, McLaughlin J R, Chung H D, Gillespie K N, Grossbcrg G T, Luque F A and Zimmerman J (1994) Alzheimer Dis Assoc Disord 8: 22-8) and that Down's syndrome patients, who develop AD in early adult life, are more prone to leukaemia than the general population (Drabkin H A and Erickson P (1995) Prog Clin Biol Res 393: 169-76; Fong C T and Brodeur G M (1987) Cancer Genet Cytogenet 28: 55-76). It is plausible therefore to hypothesize that the cell cycle regulatory failure in neurons, even in early (pre-clinical) stages of AD, might be reflected by similar cell cycle regulatory malfunction in lymphocytes.